Somarowthu Srinivas, Legiewicz Michal, Chillón Isabel, Marcia Marco, Liu Fei, Pyle Anna Marie
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Mol Cell. 2015 Apr 16;58(2):353-61. doi: 10.1016/j.molcel.2015.03.006. Epub 2015 Apr 9.
Long noncoding RNAs (lncRNAs) have recently emerged as key players in fundamental cellular processes and diseases, but their functions are poorly understood. HOTAIR is a 2,148-nt-long lncRNA molecule involved in physiological epidermal development and in pathogenic cancer progression, where it has been demonstrated to repress tumor and metastasis suppressor genes. To gain insights into the molecular mechanisms of HOTAIR, we purified it in a stable and homogenous form in vitro, and we determined its functional secondary structure through chemical probing and phylogenetic analysis. The HOTAIR structure reveals a degree of structural organization comparable to well-folded RNAs, like the group II intron, rRNA, or lncRNA steroid receptor activator. It is composed of four independently folding modules, two of which correspond to predicted protein-binding domains. Secondary structure elements that surround protein-binding motifs are evolutionarily conserved. Our work serves as a guide for "navigating" through the lncRNA HOTAIR and ultimately for understanding its function.
长链非编码RNA（lncRNAs）最近已成为细胞基本过程和疾病中的关键参与者，但其功能仍知之甚少。HOTAIR是一种长度为2148个核苷酸的lncRNA分子，参与生理性表皮发育和致病性癌症进展，在其中它已被证明可抑制肿瘤和转移抑制基因。为了深入了解HOTAIR的分子机制，我们在体外以稳定且均一的形式对其进行了纯化，并通过化学探针和系统发育分析确定了其功能性二级结构。HOTAIR结构显示出与折叠良好的RNA（如II组内含子、rRNA或lncRNA类固醇受体激活剂）相当的结构组织程度。它由四个独立折叠的模块组成，其中两个对应于预测的蛋白质结合结构域。围绕蛋白质结合基序的二级结构元件在进化上是保守的。我们的工作为“导航”通过lncRNA HOTAIR并最终理解其功能提供了指导。
